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SUMMARY

Molecular Immunology: Signal Transduction

Our research program aims to characterize the molecular mechanisms and biological impact of chemokine receptor signaling. The chemokines are a family of peptide hormones that were originally identified as chemoattractants that stimulated immune cell migration from the blood into tissues. More recent research indicates that chemokines are also potent regulators of the growth and differentiation of many cell types. The biological effects of chemokines are mediated by chemokine receptors, members of the G protein-coupled receptor (GPCR)superfamily, through the activation of Gi-type G proteins. However, the intracellular signaling pathways responsible for the biological effects of chemokines on lymphocytes and endothelial cells are largely unknown.

An example of an important chemokine receptor is CXCR4. CXCR4 stimulates the proliferation and/or death of several cell types, and mutant mice lacking either CXCR4 or its ligand, SDF-1, die from multiple developmental defects. In addition, CXCR4 binds directly to the gp120 glycoprotein of Human Immunodeficiency Virus-1 (HIV-1) and, together with HIV-1 binding to CD4, permits viral infection of T lymphocytes. The molecular mechanisms by which CXCR4 mediates these effects are poorly understood, preventing the development of drugs and treatment strategies that could be designed to exploit the powerful regulatory properties of chemokines.

Specific Research Topics

Analyzing the role and mechanisms of function of the CXCR4 chemokine receptor on T lymphocytes. Our recent results demonstrate that CXCR4 uses a Gi protein and a novel intracellular signal transduction pathway to activate the ERK mitogen-activated protein (MAP) kinases in T lymphocytes. ERK and other MAP kinases phosphorylate transcription factors in response to signaling by cell-surface receptors, thereby allowing growth factors and hormones to regulate cell growth and differentiation. Planned studies will further elucidate the molecular mechanisms involved in this pathway, and in addition, will show how ERK activation allows chemokines to regulate cytokine gene expression by T cells.

Defining the roles of chemokines on lymphoid tumor formation and dissemination, using a transgenic mouse model system. Since chemokine receptors stimulate MAP kinase proliferative signaling pathways in T lymphocytes, it is likely that chemokines contribute to lymphoid tumor development. This hypothesis will be tested using a transgenic mouse strain overexpressing the lck oncogene and a model chemokine receptor.

Characterizing chemokine actions on blood vessels during the rejection of transplanted organs. Chemokine receptors expressed by endothelial cells have recently been found to potently regulate blood vessel formation and function. This project aims to identify chemokines/chemokine receptors that are important in the rejection of transplanted organs, and will begin to identify the intracellular signaling pathways involved.

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